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Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig–coated artificial antigen-presenting cells

Nature Medicine volume 9, pages 619–625 (2003)Cite this article

Abstract

Adoptive immunotherapy holds promise as a treatment for cancer and infectious diseases, but its development has been impeded by the lack of reproducible methods for generating therapeutic numbers of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs). As a result, there are only limited reports of expansion of antigen-specific CTLs to the levels required for clinical therapy. To address this issue, artificial antigen-presenting cells (aAPCs) were made by coupling a soluble human leukocyte antigen–immunoglobulin fusion protein (HLA-Ig) and CD28-specific antibody to beads. HLA-Ig–based aAPCs were used to induce and expand CTLs specific for cytomegalovirus (CMV) or melanoma. aAPC-induced cultures showed robust antigen-specific CTL expansion over successive rounds of stimulation, resulting in the generation of clinically relevant antigen-specific CTLs that recognized endogenous antigen–major histocompatibility complex complexes presented on melanoma cells. These studies show the value of HLA-Ig–based aAPCs for reproducible expansion of disease-specific CTLs for clinical approaches to adoptive immunotherapy.

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Figure 1: Schematic of induction and expansion of peptide-specific CTLs by autologous DCs or aAPCs.
Figure 2: Induction and growth potential of Mart-1–specific CD8+ T cells stimulated with aAPCs.
Figure 3: aAPC-induced antigen-specific CTLs recognize endogenous melanoma or CMV pp65 antigen on target cells.
Figure 4: Frequency of antigen-specific CTLs after expansion with CD3-specific antibody beads or aAPCs.

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Acknowledgements

We thank M. Laumer, J. Heymann and S. Vogel for technical assistance and G. Hawkins and J. Zaia for providing the A293 cell lines. Support for this work was provided by National Institutes of Health grants AI-29575 and AI-44129, the Dr. Mildred-Scheel-Stiftung Deutsche Krebshilfe Foundation (M.O.), the Abramson Cancer Research Institute (C.H.J.) and NIH training grant DK07748 (M.V.M.).

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Authors and Affiliations

  1. Department of Pathology & Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Mathias Oelke, Dominic Didiano & Jonathan P. Schneck

  2. Abramson Family Cancer Research Institute at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Marcela V. Maus & Carl H. June

  3. Department of Hematology/Oncology, University of Regensburg, Germany

    Andreas Mackensen

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  1. Mathias Oelke
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Correspondence to Mathias Oelke.

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Competing interests

Under licensing agreements between BD-Pharmingen and Johns Hopkins University, J.P.S. is entitled to a share of the royalty received by the University on sales of DimerX products. J.P.S. is also a consultant to BD-Pharmingen. The terms of this agreement are being managed by Johns Hopkins University in accordance with its conflict-of-interest policies.

C.H.J. is an inventor on a patent describing a related technology using anti-CD28 on polystyrene paramagnetic beads (US #6,352,694). Under licensing agreements between the United States Government and Wyeth and Xcyte Therapies, Inc., C.H.J. is entitled to a share of the royalty received by the government for this related bead technology. The terms of this agreement are managed by the Office of Naval Research in accordance with the United States Government conflict-of-interest policies.

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Oelke, M., Maus, M., Didiano, D. et al. Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig–coated artificial antigen-presenting cells. Nat Med 9, 619–625 (2003). https://doi.org/10.1038/nm869

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